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EP1019058A1 - Pharmaceutical suspension comprising nevirapine hemihydrate - Google Patents

Pharmaceutical suspension comprising nevirapine hemihydrate

Info

Publication number
EP1019058A1
EP1019058A1 EP98939312A EP98939312A EP1019058A1 EP 1019058 A1 EP1019058 A1 EP 1019058A1 EP 98939312 A EP98939312 A EP 98939312A EP 98939312 A EP98939312 A EP 98939312A EP 1019058 A1 EP1019058 A1 EP 1019058A1
Authority
EP
European Patent Office
Prior art keywords
nevirapine
hemihydrate
water
particle size
microns
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP98939312A
Other languages
German (de)
French (fr)
Other versions
EP1019058B1 (en
EP1019058A4 (en
Inventor
Karl Georg Grozinger
Amale A. Hawi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharmaceuticals Inc
Original Assignee
Boehringer Ingelheim Pharmaceuticals Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=22006658&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=EP1019058(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Application filed by Boehringer Ingelheim Pharmaceuticals Inc filed Critical Boehringer Ingelheim Pharmaceuticals Inc
Publication of EP1019058A1 publication Critical patent/EP1019058A1/en
Publication of EP1019058A4 publication Critical patent/EP1019058A4/en
Application granted granted Critical
Publication of EP1019058B1 publication Critical patent/EP1019058B1/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV

Definitions

  • the invention relates to a novel composition of matter which is a pharmaceutical suspension comprising nevirapine hemihydrate.
  • Nevirapine or l l-cyclopropyl-5,1 l-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'- e][l,4]diazepin-6-one, is a known agent for the treatment of infection by HIV-1 (human immunodeficiency virus, type 1), which acts through specific inhibition of HIV- 1 reverse transcriptase. Its synthesis and use are described in various publications including, wter alia, U.S. Patent No. 5,366,972; European Patent Application No. 0 429 987, U.S. Patent Application Serial No. 08/515,093 (Attorney Docket No.
  • Viramune ® tablets a pharmaceutical comprising nevirapine in tablet form, has recently been approved by the U.S. Food and Drug Administration for use in the treatment of HIV- 1 infection.
  • the invention is an aqueous suspension of the hemihydrate form of nevirapine. It has been found, unexpectedly, that, when placed in aqueous suspension, the crystal size of the hemihydrate remains stable over time. For this reason, aqueous suspensions of nevirapine hemihydrate are pharmaceutically acceptable.
  • Anhydrous nevirapine can be made by any of several known methods, including those described in the references mentioned above.
  • the hemihydrate is conveniently produced by recrystallization of the anhydrous material from an aqueous medium. This can be accomplished by treating an aqueous suspension of the anhydrous material, which is a free base, with a strong acid, such as HC1, to yield the acid addition salt.
  • the salt is, in turn, treated with a strong base, such as NaOH, to yield the free base as a precipitate, in the hemihydrate form.
  • the precipitate is removed from the aqueous medium by filtration, washed with water and dried until the water content is between about 3.1 and 3.9% by weight. Further drying, which would convert the hemihydrate to the anhydrous form is to be avoided.
  • the term hemihydrate is intended to refer to nevirapine which contains about 0.5 mole of water.
  • the particle size of the hemihydrate should be between about 1 and 150 microns in diameter.
  • the hemihydrate produced as described above can be milled, if necessary, so that particle size will fall within this range.
  • a pharmaceutically acceptable aqueous suspension of nevirapine hemihydrate can be made by adding the hemihydrate to purified water, in ratios from 1 to 50 mg nevirapine hemihydrate to 1 mL of water, followed by agitation.
  • the formulation can additionally comprise conventional pharmaceutical additives, such as, but not limited to, suspending agents and/or viscosity thickening agents such as, for example cellulose-based polymers or synthetic polymers, preferably cross-linked polymers such as the carbomers; wetting agents such as, for example, polyethylene oxides or polyoxyethylene sorbitan fatty acid esters (polysorbates); sweetening or flavoring agents, such as sucrose; and preservatives, such as, for example, the parabens.
  • suspending agents and/or viscosity thickening agents such as, for example cellulose-based polymers or synthetic polymers, preferably cross-linked polymers such as the carbomers
  • wetting agents such as, for example, polyethylene oxides or poly
  • a glass lined reactor containing 318 Kg of nevirapine (anhydrous) is charged with 319 Kg of 37% HC1 at a flow rate to maintain the internal temperature below 35°C.
  • the mixture is agitated at 25-35°C until all material is dissolved.
  • the solution is filtered and diluted with 160 liters of purified water.
  • the solution is neutralized with a 25% sodium hydroxide solution, while maintaining the temperature below 40°C.
  • the resulting crystalline suspension is cooled to 15-20°C for 30 minutes.
  • the crystals are centrifuged and washed with purified water and dried at 30-40°C.
  • the crystals are then dried under vacuum using a conventional vacuum tumble dryer for 8-24 hours, an air circulation tray dryer for 24-72 hours, or a Titus® centrifuge dryer (TZD) for 1 to 8 hours.
  • the drug substance which is the hemihydrate, is dried until the water content is between 3.1 - 3.9% as determined by a moisture balance on 100°C for 30 min.
  • a portion of purified water is heated to approximately 70°C and the methylparaben and propylparaben are added while continuously mixing. Once the parabens have completely dissolved, the solution is allowed to cool to less than 35°C, and then the carbomer 934P is dispersed in the preservative solution while mixing. The pH is adjusted to pH 5.5 - 5.8 with 20% sodium hydroxide Solution. The gel is continually stirred for approximately 20 minutes and the pH remeasured. The sorbitol solution is added while mixing. Then the sucrose is added and mixing continued for 30 minutes. The polysorbate 80 is dissolved in a portion of purified water, the nevirapine is then added to the polysorbate 80 solution, and the mixture is homogenized for at least 40 minutes. The nevirapine/polysorbate 80 drug concentrate is thoroughly blended into the carbomer gel. The suspension is adjusted to volume or weight with purified water and blended for 30 minutes.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Molecular Biology (AREA)
  • Oncology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Steroid Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

An aqueous pharmaceutical suspension consisting essentially of nevirapine hemihydrate having a particle size between about 1 and 150 microns in diameter.

Description

PHARMACEUTICAL SUSPENSION COMPRISING NEVIRAPINE
HEMIHYDRATE
Background of the Invention
( 1 ) Field of the Invention
The invention relates to a novel composition of matter which is a pharmaceutical suspension comprising nevirapine hemihydrate.
(2) Description of the Related Art
Nevirapine, or l l-cyclopropyl-5,1 l-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'- e][l,4]diazepin-6-one, is a known agent for the treatment of infection by HIV-1 (human immunodeficiency virus, type 1), which acts through specific inhibition of HIV- 1 reverse transcriptase. Its synthesis and use are described in various publications including, wter alia, U.S. Patent No. 5,366,972; European Patent Application No. 0 429 987, U.S. Patent Application Serial No. 08/515,093 (Attorney Docket No. 9/051-3-C3, issue fee paid) and U.S Patent Application Serial No. 08/371,622 (Attorney Docket No. 1/981, issue fee paid). Viramune ® tablets, a pharmaceutical comprising nevirapine in tablet form, has recently been approved by the U.S. Food and Drug Administration for use in the treatment of HIV- 1 infection.
Angel et al. [Proc. 50th Annual Meeting of the Electron Microscopy Society of America, pp. 1326-1327 (1992)] have disclosed that nevirapine exists as the hemihydrate stable form and as the anhydrous metastable form. This same reference describes an attempt to make an aqueous suspension of nevirapine, suitable for pediatric use, from the anhydrous form of the compound. The attempt was unsuccessful because, when formulated in aqueous suspension, the anhydrous nevirapine slowly converted to the hemihydrate form, yielding crystals of the hemihydrate which, over time, grew so large as to adversely affect drug dissolution and pharmaceutical performance. Summary of the Invention
The invention is an aqueous suspension of the hemihydrate form of nevirapine. It has been found, unexpectedly, that, when placed in aqueous suspension, the crystal size of the hemihydrate remains stable over time. For this reason, aqueous suspensions of nevirapine hemihydrate are pharmaceutically acceptable.
Detailed Description of the Invention
Anhydrous nevirapine can be made by any of several known methods, including those described in the references mentioned above.
The hemihydrate is conveniently produced by recrystallization of the anhydrous material from an aqueous medium. This can be accomplished by treating an aqueous suspension of the anhydrous material, which is a free base, with a strong acid, such as HC1, to yield the acid addition salt. The salt is, in turn, treated with a strong base, such as NaOH, to yield the free base as a precipitate, in the hemihydrate form. The precipitate is removed from the aqueous medium by filtration, washed with water and dried until the water content is between about 3.1 and 3.9% by weight. Further drying, which would convert the hemihydrate to the anhydrous form is to be avoided. The term hemihydrate is intended to refer to nevirapine which contains about 0.5 mole of water.
For use in a pharmaceutically acceptable aqueous suspension, the particle size of the hemihydrate should be between about 1 and 150 microns in diameter. The hemihydrate produced as described above can be milled, if necessary, so that particle size will fall within this range.
A pharmaceutically acceptable aqueous suspension of nevirapine hemihydrate can be made by adding the hemihydrate to purified water, in ratios from 1 to 50 mg nevirapine hemihydrate to 1 mL of water, followed by agitation. The formulation can additionally comprise conventional pharmaceutical additives, such as, but not limited to, suspending agents and/or viscosity thickening agents such as, for example cellulose-based polymers or synthetic polymers, preferably cross-linked polymers such as the carbomers; wetting agents such as, for example, polyethylene oxides or polyoxyethylene sorbitan fatty acid esters (polysorbates); sweetening or flavoring agents, such as sucrose; and preservatives, such as, for example, the parabens.
By way of non-limiting description, a typical formulation in accordance with the invention would be one as described in the following table.
*20% solution prepared
The invention is further illustrated by the following non-limiting examples.
Example 1
Preparation of nevirapine hemihydrate
A glass lined reactor containing 318 Kg of nevirapine (anhydrous) is charged with 319 Kg of 37% HC1 at a flow rate to maintain the internal temperature below 35°C. The mixture is agitated at 25-35°C until all material is dissolved. The solution is filtered and diluted with 160 liters of purified water. The solution is neutralized with a 25% sodium hydroxide solution, while maintaining the temperature below 40°C. The resulting crystalline suspension is cooled to 15-20°C for 30 minutes. The crystals are centrifuged and washed with purified water and dried at 30-40°C. The crystals are then dried under vacuum using a conventional vacuum tumble dryer for 8-24 hours, an air circulation tray dryer for 24-72 hours, or a Titus® centrifuge dryer (TZD) for 1 to 8 hours. The drug substance, which is the hemihydrate, is dried until the water content is between 3.1 - 3.9% as determined by a moisture balance on 100°C for 30 min.
Example 2
Preparation of nevirapine hemihydrate
26 g of nevirapine (anhydrous) are suspended in 100 mL of water. To the stirred mixture is added 30 mL of concentrated hydrochloric acid with cooling to maintain the temperature below 30°C. After 10 to 20 minutes, the colored solution is filtered and neutralized by the addition of 14.4 g sodium hydroxide in 50 mL of water. The resulting precipitate is filtered and washed with water. The wet crystalline material is transferred to trays and dried at 35-45°C until a water content of 3.1 to 3.9% is obtained. The melting point of the resulting hemihydrate is 242-245°C and analyzes for 3.1 to 3.6% of water, or about 0.5 mole of water. Example 3
Preparation of aqueous 50 mg/5 ml pharmaceutical suspension of nevirapine hemihydrate
Composition
*20% solution prepared
Processing Method
A portion of purified water is heated to approximately 70°C and the methylparaben and propylparaben are added while continuously mixing. Once the parabens have completely dissolved, the solution is allowed to cool to less than 35°C, and then the carbomer 934P is dispersed in the preservative solution while mixing. The pH is adjusted to pH 5.5 - 5.8 with 20% sodium hydroxide Solution. The gel is continually stirred for approximately 20 minutes and the pH remeasured. The sorbitol solution is added while mixing. Then the sucrose is added and mixing continued for 30 minutes. The polysorbate 80 is dissolved in a portion of purified water, the nevirapine is then added to the polysorbate 80 solution, and the mixture is homogenized for at least 40 minutes. The nevirapine/polysorbate 80 drug concentrate is thoroughly blended into the carbomer gel. The suspension is adjusted to volume or weight with purified water and blended for 30 minutes.

Claims

What is claimed is:
1. A method for preparing an aqueous suspension of nevirapine which method comprises admixing nevirapine hemihydrate, having a particle size between about 1 and 150 microns, with water.
2. A pharmaceutical composition consisting essentially of nevirapine hemihydrate, having a particle size between about 1 and 150 microns, and water.
3. A pharmaceutical composition consisting essentially of the following constituents in the specified relative range amounts:
* 2n0% solution prepared
wherein the nevirapine particle size is between about 1 and 150 microns in diameter.
4. A pharmaceutical composition, in accordance with claim 3, consisting essentially of the following constituents in the specified relative amounts:
*20% solution prepared wherein the nevirapine particle size is between about 1 and 150 microns in diameter.
EP98939312A 1997-08-25 1998-08-11 Pharmaceutical suspension comprising nevirapine hemihydrate Expired - Lifetime EP1019058B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US5680397P 1997-08-25 1997-08-25
US56803P 1997-08-25
PCT/US1998/016581 WO1999009990A1 (en) 1997-08-25 1998-08-11 Pharmaceutical suspension comprising nevirapine hemihydrate

Publications (3)

Publication Number Publication Date
EP1019058A1 true EP1019058A1 (en) 2000-07-19
EP1019058A4 EP1019058A4 (en) 2004-11-10
EP1019058B1 EP1019058B1 (en) 2006-05-24

Family

ID=22006658

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98939312A Expired - Lifetime EP1019058B1 (en) 1997-08-25 1998-08-11 Pharmaceutical suspension comprising nevirapine hemihydrate

Country Status (38)

Country Link
US (2) US6172059B1 (en)
EP (1) EP1019058B1 (en)
JP (1) JP3472261B2 (en)
KR (1) KR100426516B1 (en)
CN (1) CN1197578C (en)
AR (2) AR016869A1 (en)
AT (1) ATE326971T1 (en)
AU (1) AU742761B2 (en)
BG (1) BG64337B1 (en)
BR (1) BR9811994B1 (en)
CA (1) CA2301646C (en)
CL (1) CL2008003111A1 (en)
CO (1) CO4970742A1 (en)
CY (1) CY1105228T1 (en)
CZ (1) CZ290667B6 (en)
DE (1) DE69834655T2 (en)
DK (1) DK1019058T3 (en)
EG (1) EG24075A (en)
ES (1) ES2265666T3 (en)
HK (1) HK1027975A1 (en)
HR (1) HRP980461B1 (en)
HU (1) HU226063B1 (en)
ID (1) ID21650A (en)
IL (1) IL134185A (en)
MY (1) MY122272A (en)
NO (1) NO326226B1 (en)
NZ (1) NZ503414A (en)
PE (1) PE105799A1 (en)
PL (1) PL192361B1 (en)
PT (1) PT1019058E (en)
RS (1) RS49808B (en)
RU (1) RU2196584C2 (en)
SA (1) SA98190680B1 (en)
TR (1) TR200000490T2 (en)
TW (1) TW450812B (en)
UA (1) UA44370C2 (en)
WO (1) WO1999009990A1 (en)
ZA (1) ZA987623B (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002092095A1 (en) * 2001-05-11 2002-11-21 Boehringer Ingelheim International Gmbh Use of nevirapine to treat or prevent lipid pathology in patients with hiv that is resistant to nevirapine
AU2003225108A1 (en) * 2002-04-23 2003-11-10 Boehringer Ingelheim Pharmaceuticals, Inc. Method for reduction of residual organic solvent in carbomer
AU2006286314A1 (en) * 2005-08-31 2007-03-08 Cipla Limited Pharmaceutical combinations containing lamivudine, stavudine and nevirapine
US20110082161A1 (en) * 2008-06-30 2011-04-07 Lieven Elvire Colette Baert Powders for reconstitution
WO2011058498A2 (en) * 2009-11-10 2011-05-19 North-West University Method for increasing the solubility of a transcriptase inhibitor composition
WO2011073907A1 (en) * 2009-12-17 2011-06-23 North-West University A polymorph form of nevirapine and its preparation

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5366972A (en) * 1989-04-20 1994-11-22 Boehringer Ingelheim Pharmaceuticals, Inc. 5,11-dihydro-6H-dipyrido(3,2-B:2',3'-E)(1,4)diazepines and their use in the prevention or treatment of HIV infection
CA2030056C (en) * 1989-11-17 1995-10-17 Karl D. Hargrave 5,11-dihydro-6h-dipyrido[3,2-b:2',3'-e][1,4]diazepines and their use in the prevention or treatment of hiv infection
US5571912A (en) * 1990-10-19 1996-11-05 Boehringer Ingelheim Pharmaceuticals, Inc. Method for the preparation of 5,11-dihydro-6h-dipyrido [3,2-b:2',3'-e][1,4]diazepines
DE4403311C1 (en) * 1994-02-03 1995-04-20 Boehringer Ingelheim Kg Process for the preparation of nevirapine (11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4-d iazepin]-6-one)

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
No further relevant documents disclosed *
See also references of WO9909990A1 *

Also Published As

Publication number Publication date
HRP980461A2 (en) 1999-06-30
SA98190680B1 (en) 2006-04-04
CA2301646A1 (en) 1999-03-04
BR9811994A (en) 2000-09-05
CO4970742A1 (en) 2000-11-07
US6255481B1 (en) 2001-07-03
AR083451A2 (en) 2013-02-27
TR200000490T2 (en) 2000-08-21
CN1197578C (en) 2005-04-20
DE69834655D1 (en) 2006-06-29
AR016869A1 (en) 2001-08-01
TW450812B (en) 2001-08-21
PE105799A1 (en) 1999-11-16
PT1019058E (en) 2006-08-31
JP3472261B2 (en) 2003-12-02
CN1268055A (en) 2000-09-27
ATE326971T1 (en) 2006-06-15
IL134185A (en) 2005-11-20
CA2301646C (en) 2008-11-18
ZA987623B (en) 2000-03-22
AU8777198A (en) 1999-03-16
HU226063B1 (en) 2008-04-28
NO326226B1 (en) 2008-10-20
CZ290667B6 (en) 2002-09-11
NO20000906L (en) 2000-02-24
YU9800A (en) 2001-12-26
ES2265666T3 (en) 2007-02-16
WO1999009990A1 (en) 1999-03-04
UA44370C2 (en) 2002-02-15
BG64337B1 (en) 2004-10-29
PL192361B1 (en) 2006-10-31
KR20010023257A (en) 2001-03-26
NO20000906D0 (en) 2000-02-24
AU742761B2 (en) 2002-01-10
US6172059B1 (en) 2001-01-09
RS49808B (en) 2008-08-07
HUP0003093A2 (en) 2001-08-28
KR100426516B1 (en) 2004-04-13
HRP980461B1 (en) 2002-08-31
EG24075A (en) 2008-05-11
DE69834655T2 (en) 2006-12-14
EP1019058B1 (en) 2006-05-24
BG104133A (en) 2000-08-31
JP2001513564A (en) 2001-09-04
ID21650A (en) 1999-07-08
MY122272A (en) 2006-04-29
CY1105228T1 (en) 2010-03-03
IL134185A0 (en) 2001-04-30
DK1019058T3 (en) 2006-06-12
HK1027975A1 (en) 2001-02-02
CL2008003111A1 (en) 2009-09-11
CZ2000694A3 (en) 2000-09-13
BR9811994B1 (en) 2013-11-19
NZ503414A (en) 2002-11-26
EP1019058A4 (en) 2004-11-10
PL338828A1 (en) 2000-11-20
RU2196584C2 (en) 2003-01-20

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